Dithiocarboxylated cephalosporins



United States Patent Q 3,239,516 DITHIOCARBOXYLATED CEPHALOSPORINS Earlev M. Van Heyningen and Carter N. Brown, both of Indianapolis, Ind., assignors to Eli Lilly and Company,

Indianapolis, Ind., a corporation of Hndiana No Drawing. Filed Jan. 18, 1965, Ser. No. 426,392 Claims. (Cl. 260-243) This invention relates to novel organic compounds and to methods for their preparation and use.

The novel compounds of the present invention are antibiotic substances having the characteristic ring structure of cephalospor-in C but having a piperazinodithiocarboxylate-derived moiety in the 3 position instead of the iacetoxylmethyl group of cephalosporin C. The novel compounds are of the class represented by the following formulas:

in which R is hydrogen, C -C alkyl, C -C alkoxy, C -C alkylrneroapto, phenyl, phenoxy, p'henylmercapto, thienyl, furyl, benzothienyl, or benzofuryl;

R is C C alkyl, C -C alkenyl, or carboxyl;

R is C C alkyl; and

R and R contain a total of not more than eight carbon atoms.

The novel compounds are readily obtained as the betaines (zwitterionic forms), or as salts with pharmaceutically acceptable cations, or as the C -C alkyl esters of the 4-carboxyl group, and it is to be understood that such forms thereof are included within the scope of the invention.

As used herein, alky refers broadly to primary, secondary, and tertiary alkyl, of both straight-chain and branched-chain configuration, wherein the number of carbon atoms therein is within the designated range, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, tert.-butyl, n-amyl, isoamyl, Z-amyl, 3-amyl, neopentyl, n-hexyl, isohexyl, 2-:hexyl, and (where within the range) n-heptyl, isoheptyl, 3-heptyl, 2-methylhexyl, and the like.

Alkenyl refers broadly to primary, secondary, and tertiary alkenyl, of both straight-chain and branched-chain configuration, including vinyl, l-propenyl, allyl, isopropenyl, crotyl, B-butenyl, l-isobutenyl, Z-isobutenyl, tertbutenyl, 4-pentenyl, 2-isopenten-yl, 5-hexenyl, neohexenyl, and the like.

Alkoxy refers to alkyl-O- groups wherein the alkyl moiety is as defined above.

Alkylmercapto refers to alkyl-S- groups wherein the alkyl moiety is as defined above.

Thienyl, benzothienyl, furyl, and benzofuryl groups may be attached at either the a or {3 position.

Pharmaceutically acceptable cations refers to the positive ionic forms of sodium, potassium, lithium, calice cium, barium, magnesium, aluminum, and other metals of acceptably low toxicity level, as well as the metalloid ammonium and a variety of organic nitrogen bases, including methylammonium, dimethylammoniu-m, trimethylammonium, tetramethylammonium, choline, the ethylammoniums, procaine, quinine, dibenzylethylenedia mine, and the like.

Halo, as used hereinafter, refers to fiuoro, chloro, bromo, or iodo.

In naming the novel compounds of the invention, it is convenient to designate the characteristic saturated fusedring B-lactam thiazine structure of the cephalosporins as cepham,

and to name the compounds as derivatives thereof, the term cephem referring to the basic ring structure with a single olefinic bond. According to this system, cephalosporin C itself would be named 7-(5-aminoadipamido)- 3-a-cetoxymethyl-3-cephem-4-carboxylic acid. More informally, it is convenient to name the compounds as derivatives of a hypothetical compound, 7-amino-3- cephem-4-carboxy1ic acid, and to specify the differences therefrom by naming the radical attached to the group in the 7 position and the piperazinodithiocarboxylate which is employed to replace the acetoxy group in the 3 position. Thus 7-athienylacetamido-3-(4'- methylpiperazinothiocarbonylthiomethyl) 3 cephem-4- carboxylic acid is more simply designated as a-thienylmethyl 4 methylpiperazinodithiocarboxylate cephalosporin.

Illustrative of the compounds lying Within the scope of the present invention are the following examples, which may exist either in zwitterionic form or as salts With nontoxic pharmaceutically acceptable cations:

7-,8-fu-rylacetamido-3 -(4- 5 -hexenyl piperazinothiocarbonylthiomethyl)-3-cephem-4-carboxy1ic acid 7-n-butylmercaptoacetamido-3- 4'-ethylpiperazino thiocarbonylthiomethyl)-3-cephem-4-carboxylic acid 7-fi-benzothienylacetamido-3-(4'-tert.-butylpiperazinoth-iocarbonylthiomethyl)-3-cephem-4carboxylic acid 7-phenylacetamido-3-(4-ethylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid 7-neopentylcarboxamido-3-(4'-(2"-hexenyl)piperazinothiocarb onyl-thiomethyl) -3-cephem-4-carboxylic acid 7-n-nonanoamido-3-(4'-allylpiperazinothiocarbonylthiomethyl -3-cephem-4-carboxylic acid 7-isovaleramido-3- (4-n-hexylpiperazinothiocarbonylth-iomethyl -3 -cephem-4-carb0xylic acid 7-n-hexyloxyacetamido-3-(4-(2"-isobutenyl)piperazinothiocarbonylthiomethyl -3 -cephem-4-canboxylic acid 7-phenoxyacetamido-3-(4-sec.-butylpiperazinothi0carbonylthiomethyl) -3-cephem-4-carboxylic acid 7-isocaproamido-3-(4-neopentylpiperazinothiocarbonylthio-met-hyl) -3-cephem-4-ca-rboxylic acid 7-phenylmercaptoacetamido-3-(4'-methylpiperazinothioca'rbonylth-iomethyl)-3-cephem-4-carboxylic acid 7-propionamido-3-(4'-crotyl-piperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid 7-B-thienylacetamido-3-(4-n-butylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid 7-ethylmercaptoacetamido-3-(4-isoamylpiperazinothiocarbonylthiomethyl)-3cephem-4-carboxylic acid 7-n-butyramido-3-(4-is-obutylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid 7-a-thienylacetamido-3-(4'-isopropylpiperazinothiocarbonylthiornethyl-S-cephem-4-carboxylic acid 7-a-benzofurylacetamido-3-(4'-vinylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxy1ic acid 7-acetamido-3-(4'-amylpiperazinothiocarbonylthior methyl) -3-cephem-4-carboxylic acid 7-methoxyacetarnido-3-(4'-methyl-4'-ethylpiperazinothiocarbonylthiomethyl)-3 cephem-4-carboxylic acid 7-aabenzothienylacetarnido-3-(4,4'-diethylpiperazinothiocarbonylthiomethyD-3-cephern-4-carboxylic acid 7-ethoxyacetamido-3-(4-ethy1-4-n-hexylpiperazinothiocarbonylthiornethyl)-3-cephem-4-carboxylic acid 7-a-furylacetamido-3-(4-ethyl-4'-vinylpiperazinothiocarbonylth-iomethyl)-3-cephem-4-carboxylic acid 7-caprylamido-3- (4-ethyl-4':n-butylpiperazinothio carbonylthiomethyl)-3-cephern-4-carboxylic acid 7-valeramido-3-(4',4-di-n-butylpiperazinothiocarbonylthiomethy-l)-3-cephem-4-carboxylic acid 7-methylmercaptoacetamido-3- (4',4-dimethylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid While the compounds of the present invention have been defined in terms of a structural formula which depicts the novel structural features of the claimed compounds and which indicates the presence thereinof certain well-known organic radicals, including alkyl, alkenyl, pheny-l, thienyl, benzothienyl, furyl, benzofuryl, and piperazino, it will be recognized by those skilled in the art, that such radicals may bear one or more sub stituents without departing in any way from the spirit of the invention and :without altering the properties of the novel compounds in such a way as would set them apart from the invention or take them outside its scope. Compounds having the novel structure of the present invention and bearing such substituents are accordingly to be considered asequivalents of the unsubstituted compounds and are to be considered to lie within the scope.

of the invention. Among such substituent atoms and radicals are halo, hydroxy, nitro, lower alkyl, trifluoromethyl, methoxy, methylmercapto, cyano, hydroxymethyl, p-hydroxyethyl, acetyl, actamido, and the like.

The compounds of the present invention are readily prepared from an appropriate derivative of 7-aminocephalosporanic acid (i.e., a derivative thereof having.

the desired acylamido group in the 7 position and the characteristic acetoxymethyl group in the 3 position) by displacement of the acetoxyl group with a 'piperazinodithiocarboxylate of appropriate structure. The reaction is conveniently carried out by dissolving a salt of the 7- aminocephalosporanic acid compound in water, adding an aqueous solution of an alkali-metal salt of the piperazinodithiocarboxylate, preferably in at least a small molar excess, and stirring and warming at ordinary or somewhat ele ated temperature for several hours. The pH of the pipe'razinodithiocarboxylate solution should not exceed about 7.58, and may be adjusted downward, if it exceeds this level, with hydrochloric acid, sulfuric acid, or the like. The reaction may be carried out at temperatures between about 25 and about 100 C., preferably around 40 to 60 C., and for periods of about one to about 24 hours or more, the time necessary for complete reaction varying inversely with the temperature, and expercent of saturation, with which conditions the start ing materials and lay-products remain largely in solution.

The yellow glass is readily purified by dissolving in chloroform, washing with 50 percent-saturated aqueous sodium chloride solution to remove impurities, ,diluting with ether, and crystallizing.

As an alternative method, 7-aminocephalosporanic acid can be reacted with the piperazinodithiocarboxylate,. and the resulting intermediate can be reacted with an appropriate acylating agent to introduce .the desired sub-'- stituent in the 7 position.-

The 4',4' disubstituted piperazinothiocarbonylthio-,,

methyl products are obtained by first preparing. the g4- monosubstituted. piperazinothiocarbonylthiomethyl cephalosporin compound :and ialkylating with .a highly re:

active alkyl, or alkenyl halide such as methylrbromide,

allyl bromide, or methyl iodide under known conditions. For this purpose,the alkyl iodides are effective,;a-s.well as the alkenyl chlorides, bromides,- and-iodides.

The desired cephalosporin C starting material, having the acetoxymethyl group in the 3 position, is readily prepared by means now well-known in the art. The most convenient and economical method involves acylating 7- aminocephalosporanic acid with an acylating agent having .the desired structure under conventional. conditions. A convenient acylating agent is, for example, the appropriate R -substituted, acetyl chloride or bromide. The acylation is carried out in .water or in, an appropriate organic solvent, preferably under substantially neutral conditions and preferably at reduced temperature, i.e., above the freezing point ofthe reaction mixture and up to about 20 'C. Ina typical procedure, 7-am-inoceph-z. alosporanic acid is commingled with aqueous 50 VOlUlDG-r:

percent acetone and a suflicient quantity of sodium biscarbonate to promote solution, the. concentration of 7- aminocephalosporanic acid being about one to about four percent by weight;

tracted :withethyl acetate or'other immiscible .organic solvent. The ethyl acetate extract is adjusted to around pH 4.5 with potassiumhy'droxide or other base and, is back-extracted into water. The :water solution is separated and evaporated to dryness. The residue is taken up in the minimum quantity of water, and the acylated product is precipitated by adding a large excess of acetone and, if necessary, ether.

ent invention are conveniently prepared by the method of Bogemann, Methoden der Organischen Chemie v(Houben- Weyl), Stuttgart: Georg Thiems Verlag,:1955, volume 9,-

page, 826. A solution of; sodium-hydroxide (0.2 mole) in 35 ml. of Water is cooled to 0 C. and mixed with an the alkali-metal salts of 4-methyl, 4-ethyl, 4-isopropyl,

4 n-propyl, 4-isobutyl, 4-n-butyl, 4-(2-butyl), 4-n-amyl,

4-neopentyl, 4-n-hexyl, and .the other. piperazinodithio-. carboxylates employed in the present invention, as well as the analogous 4-alkenyl compounds within the contemplation of the present disclosure. The results of typical preparations of, the sodiurnsalts are given in the following table, where the substituent'at the 4 position. of. the.

piperazine ring is referred to as R The solution is cooled to around0' to 5 (3., and a solution oftheacylating agent is added in about 20 percent excess, wit-h stirring and cooling; The mixture is then allowed to warm to room tempera-u ture, after which it is acidifiedto around pH 2 and ex-,

v The. crystalline material obtamed thereby-1s filtered, Washed with acetone, and dried. 1 The piperazin'odithiocarboxylates employed in the pres-' precipitates as the sodium.

h All compounds melted with decomposition.

The invention will be more readily understood from the following operating examples, which are submitted as illustrations only, and not by way of limitation.

In all cases, the following procedure was employed with only slight variations to prepare the designated compound. A 0.0012 mole portion of the appropriately substituted sodium 7-acylamidocephalosporanate and an equimolar amount of the appropriate sodium piperazinodithiocarboxylate were dissolved in ml. of water and heated at 40-45 C. in a thermostated oil bath for 24 hours, then filtered to remove a small quantity of insoluble byproduct. The desired product was precipitated as a yellow glass by addition of an equal volume of aqueous saturated sodium chloride solution and chilling for several hours. The supernatant solution was decanted from the solid phase and the solid was dissolved in 25 to 50 ml. of chloroform. The chloroform solution was washed about 10 times with successive 1215 ml. portions of 50 percent saturated aqueous sodium chloride solution. In some cases, especially toward the end of the wash, troublesome emulsions were formed, but were readily broken by centrifuging. The washing was conveniently followed by qualitative ultraviolet spectra of the wash solutions; disappearance of the spectrum for starting material and appearance of the spectrum for the product indicated when washing was complete. The Washed chloroform solution was evaporated to half volume or less, then diluted with ether, and chilled. The sodium salt of the desired product separated as a fine powder, which was centrifuged and dried under vacuum.

The melting points of the products were not sharp, owing to the fact that the compounds tend to decompose at or around their melting point, and the melting points therefore vary, depending upon the temperature of the meltingpoint block when the compounds were first applied. All of the products, however, had infrared spectra consistent with the expected structure and gave one spot against Bacillus subtilis in bio-autographs of paper chr0- matograms, which were developed with methyl ethyl ketone saturated with water. These data, together with the ultraviolet spectra, titrations, and analyses, were sufllcient to characterize the substances fully.

EXAMPLE 1 a-Thienylmelhyl 4-methylpiperazinodithiocarboxylate cephalosporin 7-u-thienylacetarnido-3-(4-methylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid sodium salt was obtained from 7-a-thienylacetamidocephalosporanic acid and 4-methylpiperazinodithiocarboxylate. Yield, 23.5 percent of theory. pK,,, 4.6 and 6.1. Ultraviolet absorption maximum at 272 m (e:2l,600).

Analysis.Calc.: C 44.92, H 4.33, N 10.48. Found: C 44.77, H 4.50, N 10.28.

EXAMPLE 2 a-Thienylmethyl 4-ethylpiperazinodithiocarboxylate cephalosporin 7 a-thienylacetamido-3-(4'-ethylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylicacid sodium salt was obtained from 7-ix-thienylacetamido cephalosporanic acid and 4-ethylpiperazinodithiocarboxylate. Yield, 6.1 percent of theory. Ultraviolet absorption maxima at 242 and 270 mu. (6: 16,550 and 19,500, respectively).

Analysis.Calc.: C 45.97, H 4.59, N 10.21. C 46.06, H 4.65, N 10.18.

EXAMPLE 3 u-Thienylmethyl 4-n-pr0pylpz'perazinodithiacarboxylate cephalosporin Found:

7 u-thienylacetamido-3-(4'-n-propylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid sodium salt was obtained from 7-a-thienylacetamidocephalosporanic acid and 4-n-propylpiperazinodithiocarboxylate. Yield, 25.2 percent of theory. pK 4.4 and 6.2. Ultraviolet absorption maximum at 270 mu (e=22,200).

Analysis-Cale; C 46.95, H 4.83, N 9.96. Found: C 47.09, H 4.79, N 9.91.

EXAMPLE 4 a-Thienylmethyl 4-is0pr0pylpiperazinodithiocarboxylate cephalosporin EXAMPLE 5 a-Thz'enylmethyl 4-n-butylpiperazin0dithiocarboxylate cephalosporin 7 0c thienylacetamido-Ii-(4-n-butylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid sodium salt was obtained from 7-a-thienylacetamidocephalosporanic acid and 4-n-butylpiperazinodithiocarboxylate. Yield, 23.2 percent of theory. pK 4.5 and 6.25. Ultraviolet absorption maximum at 271 m (e:2l,600).

Analysis.Calc.: C 47.89, H 5.06, N 9.71. C 47.61, H 5.25, N 9.48.

Found:

EXAMPLE 6 a-Thienylmethyl 4-n-amylpiperazinodithiocarboxylate cephalosporin 7 cc thienylacetamido-3-(4'-n-amylpiperazinothiocarbonylthiomethyl)-3-cephern-4-carboxylic acid sodium salt was obtained from 7-a-thienylacetamidocephalosporanic acid and 4-n-amylpiperazinodithiocarboxylate. Yield, 14.2 percent of theory. pK 4.4 and 6.2. Ultraviolet absorption maximum at 270 mu (e=19,700).

Analysis.-Calc.: C 47.41, H 5.42, N 9.20. Found: C 47.06, H 5.36, N 9.12.

7 EXAMPLE 7 a-Thienylmethyl 4-(/3-hydr0xyethyl)piperazinodithiocarboxylaze cephalosporin 7 zx thienylacetamido 3-(4'-(fi-hydroxyethyl)piperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid sodium salt was obtained from 7-a-thienylacetamidocephalosporanic acid and 4-(li-hydroxyethyl)piperazinodithiocarboxylate. The chloroform-insoluble crude product was precipitated as the Zwitterionic compound at pH 5.5. The solid was filtered off, washed with water, and redissolved with aqueous 1 N sodium hydroxide at pH 7.2.

The solution was evaporated to dryness under vacuum, and the residue was recrystallized from methanol-isopropanol. Yield, 9.6 percent of theory. pK,,, 4.4 and 5.8. Ultraviolet absorption maxima at 235 and 270 m (e=16,500 and 20,500, respectively).

Analyris.Calc.: C 44.66, H 4.46, N 9.92. Found: C 44.88, H 4.40, N 9.98.

EXAMPLE 8 a-Thienylmethyl 2-carboxy-4-methylpiperazinodithiocarboxylate cephalosporin 7 a-thienylacetamido-3-(2'-carboxy-4'-methylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid disodium salt was obtained from 7-a-thienylacetan1idocephalosporanic acid and 2-carboxy-4-methylpiperazinor dithiocarboxylate. The latter was used in the form of the crude disodium salt. The reaction was carried out heating at 70 C. for 2 hours. When nothing precipitated on addition of saturated sodium chloride solution,.the diacid was precipitated at pH 2. The solid was filtered off and redissolved in dilute sodium hydroxide at pH 6.5. The solution was evaporated to dryness under vacuum, and the residue was recrystallized from methanol-isopropanol. Yield, 6.6 percent of theory. pK',,, 4.7 and 6.85. Ultraviolet absorption maxima at 234 and 272 m (e=15,400 and 17,300, respectively).

Analysis.-Calc.: C 39.62,.H 4.09, N 8.80. Found: C 39.70, H 4.11, N 8.25.

EXAMPLE 9 Phenylmercaptomelhyl 4-methylpiperazinodithiocarboxylate cephalosporin 7 phenylmereaptoacetamido 3-(4-methylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid sodium salt was obtained from7-phenylmercaptoacetarnido cephalosporanic acid and 4-methylpiperazinodithiocarboxylate. Yield, 18.9 percent of theory. pK 4.5 and 6.05. Ultraviolet absorption maximum at 256 m (e=17,390).

Analysis.Calc.: C 47.12, H 4.49, N 9.99. Found:

C 48.80, H 4.80, N 9.04.

EXAMPLE 10 a-Thienylmethyl 4-carbeth0xypiperazinodithiocarboxylate cephalosporin 7 a-thienylacetamido-3-(4'-carbethoxypiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid sodiurn' salt was obtained from. 7-u-thienylacetamidocephalosporanic acid and 4-carbethoxypiperazinodithiocarboxylate. Yield, 45.3 percent of theory. pK 4.98. Ultraviolet absorption maximum at 273 m (s:24,400).

Analysis.Calc.: C 44.58, H 4.25, N 9.45. Found: C 44.38, H 4.41, N 9.49.

The quaternary piperazinium compounds of the following examples were prepared in the following way.

The 4-alkylpiperazinodithiocarboxylate derivative of the cephalosporin was prepared as described in the foregoing examples, except that the chloroform solution was washed only twice with the sodium chloride solution, and was.

then evaporated and the residue dried. The crude sodium by acidifying the aqueous reaction mixture to pH 8 and salt thus obtained (about 0.01 mole) was'dissolved in mi. of dry chloroform and commingled with a solution'of 0.0105 mole of the appropriate alkyl or: alkenyl. halide in 10 ml. of chloroform. The mixture was held in a stopperedlflask at room temperature with occasional shaking for 4-7 days, during which time there was a gradual precipitation of solid. The; cream-colored. pre= cipitate was filtered. and air-dried, then -triturated with The water to remove .co-precipitated sodium iodide. product, which was a yellow tafi'y quite insoluble in water, was dissolved in dimethylformamide (25-35 ml./g.) by

warming gentlyand adding water cautiously until the cloudiness cleared. Then tetrahydrofuran (5-10 volumes) was added, and the turbid mixture was cooled, The resulting precipitate .was separated by centrifuging,

washed with ether, and vacuum-dried.

EXAMPLE 11 a-Thienylmethyl 4,4-dimethylpiperazinodithiocarboxylate cephalou'porin 7 0c thienylacetarnidoi- 3 (4,4' dimethylpiperazinothiocarbonylthiomethyl) 3 cephem 4 carboXylic acid betaine Wasobtained from 7-a-thienylacetamido-3- (4 methylpiper-azinothiocarbonylthiomethyl) 3 cephem-4-carboxylic acid andmethyliodide. The product betaine, unlike the other 4',4 quaternaries, wasinsolu-ble in dimethylformamide. It was therefore triturated in warm dimethylformamide, filtered, and washed with water, then with ether, and dried. Yield, 48.0 percent of theory. pK 4.58. Ultraviolet absorption maximum at 269 m (e=20,400).

Analysis.-Calc.: C 47.88,-H 4.97, N 10.64. Found: C 47.79, H 5.42, N 10.43.

EXAMPLE 12 u-Thienylmethyl 4-methyl-441-propylpiperazinodithiocarboxylate cephalo'sporin 7 u thienylacetamido 3 (4' methyl 4' n propylpiperazinothiocarbonylthiomethyl) 3 cephem 4- carboxylic acid betainewas obtained from 7-kx-thienylacetamido 3 (4 n propylpiperazinothiocarbonylthiomethyl)-3-cephern-4-canboxylic.acid and methyl iodide.

Yield, 26.4 percent of theory. pK 4.6.: Ultraviolet absorption maximum at 273 Ill .0 (e=23,000)-.

Analysis.-Calc.: C 49.79, H 5.45, N 10.10. Found: C 49.67, H 5.55, N982.

EXAMPLE 14 a-Thienylmethyl 4-methyl-4-n-bulylpiperazinodithiocarboxylate cephalosporin 7 a thienylacetarnido 3 (4' methyl 4"- n butylp1perazinothio'carbonylthiomethyl 3 cephem 4 carboxylic acid betaine .was obtained from 7-a-thienylacet-.

amido 3 (4' nbutylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid and methyl iodide.v

Yield, 25 percent of theory: pK',,, 4.6; Ultraviolet absorption maximum at 271 m (e -22,900);

Analysis.Ca1c.: C 50.67, H 5.67, N 9.85. Found: C 50.56, H564, N 9.89.

The compounds of the present invention are characterized by resistance to the destructive action of penicillinase, and by a high degree of activity against a broad range of both Gram-positive and Gram-negative pathogens.

We claim: 1. A compound selected from the group consisting of:

R is a member of the group consisting of hydrogen,

C -C alkyl, C C- alkoxy, C -C alkylmercapto, phenyl, phenoxy, phenylmercapto, thienyl, furyl, benzothienyl, and benzofuryl;

R is a member of the group consisting of C -C alkyl,

C -C alkenyl, and carboxyl;

R is C -C alkyl; and

R and R contain a total of not more than eight carbon atoms;

and the salts of said compounds with pha-rmaceutically acceptable cations,

and the C -C alkyl esters of the 4-carboxyl group.

2. 7 a thienylacetamido 3 (4 methylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid.

3. 7 a thienylacetamido 3 (4' ethylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid.

4. 7 a thienylacetamido 3 (4 n propylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid.

5. 7 a thienylacetamido 3 (4 isopropylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid.

6. 7 oz thienylacetamido 3 (4 r1 butylpipera- Zinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid.

7. 7 a thienylacetamido 3 (4 n amylpiperazinothiocarbonylthiomethyl)-3-cephem-4-carboxylic acid.

8. 7 a thienylacetamido 3 (4 ([3 hydroxyethyl)piperazinothiocarbonylthiomethyl) 3 cephem- 4-carboxylic acid.

9. 7 a thienylacetamido 3 (2' carboxy 4'- methylpiperazinothiocarbonylthiomethyl) 3 cephem 4- carboxylic acid.

10. 7 phenylmercaptoacetamido 3 (4 methylpiperazinothiooarbonylthiomethyl) 3 cephem 4 carboxylic acid.

11. 7 0c thienylacetamido 3 (4' carbethoxypiperazinothiocarbonylthiomethyl) 3 cephem 4 carboxylic acid.

12. 7 a thienylacetarnido 3 (4',4 dimethylpiperazinothiocarbonylthiomethyl) 3 cephem 4 carboxylic acid.

13. 7 a thienylacetamido 3 (4 methyl 4' npropylpiperazinothiocarbonylthiomethyl) 3 cephem- 4-carboxylic acid.

14. 7 0c thienylacetamido 3 (4 methyl 4 allylpiperazinothiocarbonylthiomethyl) 3 cephem 4- carboxylic acid.

15. 7 oz thienylacetamido 3 (4' methyl 4' nbutylpiperazinothiocarbonylthiomethyl) 3 cephem 4- carboxylic acid.

No references cited.

IRVING MARCUS, Primary Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 